Chromatin structure contains important regulatory information for all DNA-based processes, such as transcription, repair, and replication. The polycomb group (PcG) and trithorax group (TrxG) protein complexes regulate chromatin structure through evolutionarily conserved mechanisms in eukaryotes for gene silencing or activation, respectively (Schuettengruber et al., 2007). Polycomb proteins assemble into at least two distinct complexes, the polycomb repressive complexes 1 and 2 (PRC1 and PRC2, respectively). Several lines of evidence suggest that PCR2 is involved in recruiting the PRC1 complex to promoters of their common target genes. A delicate balance of PcG protein levels ensures proper cell proliferation and normal tissue homeostasis while abnormal expression patterns or genomic alterations in PcG proteins can result in transcriptional dysregulation and cause various diseases including cancer (Laugesen and Helin, 2014).
Histone tails extruding from the nucleosome core are subject to multiple modifications including phosphorylation, acetylation, methylation, ubiquitination, and sumoylation. Histone modifications exert substantial influence on transcriptional regulation by modulating higher-order chromatin structures. There are two functional states of chromatin: euchromatin and heterochromatin, which are transcriptionally active and inactive, respectively. Some histone modifications, such as tri-methylation at histone 4 lysine 20 (H4K20me3), histone 3 lysine 9 (H3K9me3) or lysine 79 (H3K79me3), predominantly occur in constitutive heterochromatin domains; whereas others, such as tri-methylation at histone 3 lysine 4 (H3K4me3) and acetylation at histone 3 lysine 27 (H3K27ac), are regarded as hallmarks of actively transcribed regions in euchromatin. Tri-methylation at histone 3 lysine 27 (H3K27me3) is generally associated with transcriptional rexpression in higher eukaryotes (Cao et al., 2002; Czermin et al., 2002; Muller et al., 2002). Bivalent domains, termed by the paradoxical coexistence of repressive mark H3K27me3 and activating mark H3K4me3, keep developmental genes in a silent but poised state for activation upon differentiation (Chen and Dent, 2014).
Enhancer of zeste homolog 2 (EZH2) is core component of PRC2 that catalyzes the di- and tri-methylation at histone H3 lysine 27 (H3K27me2/3). EZH2 plays a critical role in normal development, and EZH2-deficient mice died at early stage of embryo due to the failure of implantation and gastrulation (O'Carroll et al., 2001). Somatic mutations in the SET domain of EZH2 (e.g., Y641N) resulting hyperactivity of the enzyme have been identified in a large portion of follicular and diffuse large B-cell lymphomas, implicating a driver function of EZH2 in cancer formation (Beguelin et al., 2013; Morin et al., 2010). A GEM model with conditional expression of mutant EZH2 (Y641N) was recently developed, which induced germinal center (GC) hyperplasia and accelerates lymphomagenesis in cooperation with BCL2 (Beguelin et al., 2013).